DESCRIPTION Abstract One of the major challenges in the post-genomic era is understanding the complex web of genetic, developmental, physiological, and environmental interactions underlying continuous trait variation, including susceptibility to disease. Although there have been notable successes in mapping Mendelian traits, there have been relatively few successes in the dissection of the genetic architecture of complex traits involving multiple loci and environmental factors. We know even less about the genetics of complex trait variability in Africa, a region that had been under-represented in human genetics studies. Recent advances in the development of high-throughput genotyping, gene expression, and sequencing technologies now facilitate approaches that incorporate genotype and gene expression data from thousands of loci in thousands of individuals. A systems biology approach, which incorporates information about genetic interactions and transcription networks, and focuses on how naturally occurring genetic variants perturb these networks, may be more successful than traditional approaches for dissecting the genetic architecture of complex variable traits and for identifying functional variants. Equally important is understanding how these molecular networks are influenced by environmental factors including diet, lifestyle, and infectious disease status. For these reasons, I plan to use a novel integrative genomics approach, incorporating genomic, transcriptomic, and metabolomic data obtained from genetically, ethnically and geographically diverse Africans living in distinct environments. These data will provide, for the first time, a detailed knowledge of the comparative physiology of genetically and culturally diverse Africans and a detailed understanding of human evolutionary history in Africa. I will use a systems and evolutionary biology approach to identify genetic and environmental factors that influence complex physiologic traits, including disease susceptibility, in these populations.